The specific objectives of the proposed study are fourfold. 1. To establish that the antiviral activities of human interferons in cells of other hosts bear the antigenic imprint of the producer cell. 2. To demonstrate that animals whose cells are protected from viral infection by human interferons do not develop neutralizing antibodies against the human antiviral principle(s) active in their own cells, although they can form antibodies which neutralize the effect of human interferons in human and other heterologous cells. 3. To provide experimental evidence that the active sites governing antiviral expression of human interferons in heterologous cells reside in single molecules rather than in multiple factors. 4. To ascertain whether interferon species segregated by virtue of distinct physico-chemical properties from the same preparation differ in their protective effects on heterologous cells. Interferons produced in human leukocytes, fibroblasts, and lymphoblastoid cells, after partial purification by affinity chromatography on anti-interferon globulin-Sepharose, will be examined for antiviral activity in mouse, bovine, porcine and hamster cells. In neutralization tests with antibodies raised in rabbits against human and other mammalian interferons, antigenic determinations on human interferons responsible for heterospecific protection will be defined. Their association with single molecules should be disclosed by affinity chromatography of human interferons on mouse and hamster anti-interferon globulins deficient in antibodies against mouse or hamster protective human factors. Individual components isolated from human interferons in highly purified form on hydroxylapatite and by SDS-polyacrylamide gel electrophoresis will be analyzed according to the above methods for the distribution of heterospecific effects and corresponding antigenic determinants on the interferon molecule.